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COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage

Authors

  • Yi-Chinn Weng PhD,

    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
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  • Akshata Sonni BS,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
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  • Cassandre Labelle-Dumais PhD,

    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
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  • Michelle de Leau MSc,

    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
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  • W. Berkeley Kauffman MSc,

    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
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  • Marion Jeanne PhD,

    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
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  • Alessandro Biffi MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Hemorrhagic Stroke Research Group, Department of Neurology, Massachusetts General Hospital, Boston, MA
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  • Steven M. Greenberg MD, PhD,

    1. Hemorrhagic Stroke Research Group, Department of Neurology, Massachusetts General Hospital, Boston, MA
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  • Jonathan Rosand MD, MSc,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Hemorrhagic Stroke Research Group, Department of Neurology, Massachusetts General Hospital, Boston, MA
    3. Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA
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  • Douglas B. Gould PhD

    Corresponding author
    1. Departments of Ophthalmology, UCSF School of Medicine, San Francisco, CA
    2. Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA
    • 10 Koret Way, Rm. K235, San Francisco, CA 94122
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Abstract

Objective:

Mutations in the type IV collagen alpha 1 gene (COL4A1) cause dominantly inherited cerebrovascular disease. We seek to determine the extent to which COL4A1 mutations contribute to sporadic, nonfamilial, intracerebral hemorrhages (ICHs).

Methods:

We sequenced COL4A1 in 96 patients with sporadic ICH. The presence of putative mutations was tested in 145 ICH-free controls. The effects of rare coding variants on COL4A1 biosynthesis were compared to previously validated mutations that cause porencephaly, small vessel disease, and hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) syndrome.

Results:

We identified 2 rare nonsynonymous variants in ICH patients that were not detected in controls, 2 rare nonsynonymous variants in controls that were not detected in patients, and 2 common nonsynonymous variants that were detected in patients and controls. No variant found in controls affected COL4A1 biosynthesis. Both variants (COL4A1P352L and COL4A1R538G) found only in patients changed conserved amino acids and impaired COL4A1 secretion much like mutations that cause familial cerebrovascular disease.

Interpretation:

This is the first assessment of the broader role for COL4A1 mutations in the etiology of ICH beyond a contribution to rare and severe familial cases and the first functional evaluation of the biosynthetic consequences of an allelic series of COL4A1 mutations that cause cerebrovascular disease. We identified 2 putative mutations in 96 patients with sporadic ICH and showed that these and other previously validated mutations inhibit secretion of COL4A1. Our data support the hypothesis that increased intracellular accumulation of COL4A1, decreased extracellular COL4A1, or both, contribute to sporadic cerebrovascular disease and ICH. ANN NEUROL 2012;

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